TY - JOUR

T1 - Pharmacological HIF1 Inhibition Eliminates Downregulation of the Pentose Phosphate Pathway and Prevents Neuronal Apoptosis in Rat Hippocampus Caused by Severe Hypoxia

AU - Vetrovoy, Oleg

AU - Sarieva, Kseniia

AU - Lomert, Ekaterina

AU - Nimiritsky, Peter

AU - Eschenko, Natalia

AU - Galkina, Olga

AU - Lyanguzov, Andrey

AU - Tyulkova, Ekaterina

AU - Rybnikova, Elena

PY - 2020/5/1

Y1 - 2020/5/1

N2 - The pentose phosphate pathway (PPP) of glucose metabolism in the brain serves as a primary source of NADPH which in turn plays a crucial role in multiple cellular processes, including maintenance of redox homeostasis and antioxidant defense. In our model of protective mild hypobaric hypoxia in rats (3MHH), an inverse correlation between hypoxia-inducible factor-1 (HIF1) activity and mRNA levels of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP, was observed. In the present study, it was demonstrated that severe hypobaric hypoxia (SH) induced short-term upregulation of HIF1 alpha-subunit (HIF1α) in the hippocampal CA1 subfield and decreased the activity of G6PD. The levels of NADPH were also reduced, promoting oxidative stress, triggering apoptosis, and neuronal loss. Injection of a HIF1 inhibitor (HIF1i), topotecan hydrochloride (5 mg/kg, i.p.), before SH prevented the upregulation of HIF1α and normalized G6PD activity. In addition, HIF1i injection caused an increase in NADPH levels, normalization of total glutathione levels and of the cellular redox status as well as suppression of free-radical and apoptotic processes. These results demonstrate a new molecular mechanism of post-hypoxic cerebral pathology development which involves HIF1-dependent PPP depletion and support a recently suggested injurious role of HIF1 activation in the acute phase of cerebral hypoxia/ischemia. Application of PPP stimulators in early post-hypoxic/ischemic period might represent a promising neuroprotective strategy. [Figure not available: see fulltext.].

AB - The pentose phosphate pathway (PPP) of glucose metabolism in the brain serves as a primary source of NADPH which in turn plays a crucial role in multiple cellular processes, including maintenance of redox homeostasis and antioxidant defense. In our model of protective mild hypobaric hypoxia in rats (3MHH), an inverse correlation between hypoxia-inducible factor-1 (HIF1) activity and mRNA levels of glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP, was observed. In the present study, it was demonstrated that severe hypobaric hypoxia (SH) induced short-term upregulation of HIF1 alpha-subunit (HIF1α) in the hippocampal CA1 subfield and decreased the activity of G6PD. The levels of NADPH were also reduced, promoting oxidative stress, triggering apoptosis, and neuronal loss. Injection of a HIF1 inhibitor (HIF1i), topotecan hydrochloride (5 mg/kg, i.p.), before SH prevented the upregulation of HIF1α and normalized G6PD activity. In addition, HIF1i injection caused an increase in NADPH levels, normalization of total glutathione levels and of the cellular redox status as well as suppression of free-radical and apoptotic processes. These results demonstrate a new molecular mechanism of post-hypoxic cerebral pathology development which involves HIF1-dependent PPP depletion and support a recently suggested injurious role of HIF1 activation in the acute phase of cerebral hypoxia/ischemia. Application of PPP stimulators in early post-hypoxic/ischemic period might represent a promising neuroprotective strategy. [Figure not available: see fulltext.].

KW - HIF1

KW - Neuronal injury and loss

KW - Neuroprotection

KW - Oxidative stress

KW - Pentose phosphate pathway

KW - Severe hypoxia

KW - OXIDATIVE STRESS

KW - SEVERE HYPOBARIC HYPOXIA

KW - LIPID-PEROXIDATION

KW - BRAIN-INJURY

KW - MECHANISMS

KW - GLUCOSE-METABOLISM

KW - GLUTATHIONE

KW - HIF-1-ALPHA

KW - UP-REGULATION

KW - EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=85077171455&partnerID=8YFLogxK

U2 - 10.1007/s12031-019-01469-8

DO - 10.1007/s12031-019-01469-8

M3 - Article

C2 - 31865524

AN - SCOPUS:85077171455

VL - 70

SP - 635

EP - 646

JO - Journal of Molecular Neuroscience

JF - Journal of Molecular Neuroscience

SN - 0895-8696

IS - 5

ER -